Generation and preclinical assessment of depemokimab, an enhanced IL-5 antagonist monoclonal antibody
Martin Orecchia, Katherine Welbeck, Jason Dexter, Laura Hook, Chika Akinseye, Marcin Kot, Alan J. Lewis, Don O. Somers, Tejinder Bhinder, Paul Hamblin, Sarah Elsey, David Willé, Steven Grant
Abstract
This study describes the affinity maturation, molecular engineering, and preclinical assessment of depemokimab, an enhanced anti-interleukin-5 antagonist antibody. The molecular design objective for depemokimab was to generate a therapeutic antibody enabling a less frequent dosing regimen of once every 6 months compared with every 4 weeks for mepolizumab. Mepolizumab is a marketed monoclonal antibody used as an add-on prescription maintenance treatment for patients with severe asthma with an eosinophilic phenotype and other eosinophilic-associated disorders. A complementarity-determining region restricted affinity maturation strategy was used where affinity improved interleukin-5 binding antibody variants were subject to affinity driven selective pressure and identified using the Adimab yeast-based platform. Improved complementarity-determining region variants were combined with serum half-life extending amino acid mutations introduced into the fragment crystallizable region of the antibody. When compared with mepolizumab, depemokimab demonstrated improved in vitro interleukin-5 neutralization in a TF-1 (human erythroleukemia) functional cell assay. In vivo , depemokimab displayed significantly extended pharmacokinetic performance and pharmacodynamic duration determined via eosinophil suppression in cynomolgus monkey ( Macaca fascicularis ). These data provide compelling evidence that a less frequent dosing regimen for depemokimab in humans is possible and supported the advancement of depemokimab into a Phase I study in patients with asthma.